The occurrence of tuberculosis among persons with human immuno-
deficiency virus (HIV) infection has prompted the development of
guidelines for the management of those who may have both
tuberculous
and HIV infections (7). These guidelines include the recommendation
that all persons who are known to be infected with HIV, or are at
increased risk of HIV infection, receive a tuberculin skin test
(Mantoux test with tuberculin units 5 {TU} of purified protein
derivative {PPD}-tuberculin). Those persons who have at least a 5
mm
reaction to PPD should be considered for 1 year of isoniazid
preventive therapy, unless otherwise contraindicated.

The Division of Tuberculosis Elimination (DTBE) in CDC's Center
for Prevention Services has considered requests for information
regarding screening for anergy among persons infected with HIV who
are
at increased risk of tuberculous infection but do not react to a
tuberculin skin test. Recent reports have suggested that anergy to
tuberculin among asymptomatic persons infected with HIV may be more
common than initially suspected. Thus, the guidelines presented
below
are intended for the evaluation and management of persons who may
have
tuberculous infection and HIV-induced anergy to delayed-type
hypersen-
sitivity (DTH) skin test antigens, including PPD-tuberculin. These
guidelines were developed by DTBE and gratefully acknowledge: Col.
John Brundage, M.D., Washington, DC; Sotiros Chaparas, Ph.D.,
Baltimore, MD; Gail Gutierrez, R.N., Los Angeles, CA; Norman
Markowitz, M.D., Detroit, MI, Edward Nardell, M.D., Cambridge, MA;
Kenrad Nelson, M.D., Baltimore, MD; and Lee Reichman, M.D., Newark,
NJ.

ASSESSMENT OF DTH RESPONSIVENESS

Many diseases and infections, including cancer and certain
viral
infections (especially HIV infection), and some immunosuppressive
drugs may result in a transient or continuing suppression of
cellular
hypersensitivity mediated by T-lymphocytes. The degree of
suppression
may be reflected in a patient's inability to mount a DTH response
to
one or several skin-test antigens.

Most healthy people have a DTH response to several bacterial,
viral, and fungal antigens. However, only four are available as
standardized antigens for use by a Mantoux-type procedure (0.1 ml
of
antigen administered intracutaneously): tuberculin, coccidioidin,
histoplasmin, and mumps. No other antigens intended for assessing a
person's ability to elicit a DTH response have been standardized
for
this use by the Mantoux procedure.

Only a small proportion of the population is sensitive to
tuberculin; sensitivity to histoplasmin and coccidioidin is
restricted
to endemic regions of infections. Therefore, some investigators
have
used antigen preparations, such as trichophyton, intended for the
diagnosis and/or treatment of immediate type hypersensitivity
reactions. Other investigators have found tetanus toxoid to be
useful
in assessing DTH responsiveness. However, none of these products
are
licensed for use as DTH skin-test antigens, and none are certified
for
lot-to-lot reproducibility for this purpose.

The Food and Drug Administration has licensed for the
evaluation
of cellular hypersensitivity a multiple puncture device (MULTITEST
CMI(R)) that delivers seven DTH antigens percutaneously. Even
though
the concentration of antigen loaded onto such devices may be
consistent from lot to lot, the amount of antigen deposited in the
skin is unknown and may vary because of the nature of the subject's
skin and the method of administration. Although the sensitivity of
these tests may be high, their use as quantitative tools for
assessment of anergy is limited. In contrast, responses to antigens
administered by a Mantoux-type procedure, in which a known quantity
of
a known concentration of a standardized antigen is deposited in the
skin, may be more accurate indicators of a waning or increasing
cellular hypersensitivity.

DTH RESPONSE IN HIV INFECTION

Investigators have evaluated groups of persons with HIV
infection
for their ability to mount a DTH response and have related the
results
to other measures of HIV infection -- most commonly, CD4
T-lymphocyte
counts.

Since 1985, in eight U.S. Army medical centers, approximately
8,000 clinical evaluations have been conducted among more than
2,000
individuals diagnosed with HIV-1 infection (Brundage J, Walter-Reed
Army Institute for Research, personal communication). Clinical
evalu-
ations were conducted to assess the Walter Reed Clinical Stage and
included assays of CD4 counts and responses to a panel of DTH skin
tests (including Candida albicans, mumps, trichophyton, and tetanus
toxoid). Cutaneous anergy, defined as no reaction to any of the
skin
tests, was reported in <10% of evaluations conducted when CD4 counts were 500/mm superscript 3. In all CD4 defined strata, particularly those>200/mm superscript 3, the presence of anergy had prognostic
significance with regard to the time of occurrence of the first
opportunistic infection (2).

Among antigens routinely used in Army medical centers, mumps
produced more positive reactions than Candida or tetanus toxoid.
Trichophyton reactivity occurred in <15% of both HIV-infected and HIV- uninfected persons. However, studies of skin-test performance at a single Army medical center indicated that Candida and tetanus toxoid in 1:10 dilutions performed as well as mumps (Birx-Raybuck D, Walter- Reed Army Institute for Research, personal communication). Among persons with CD4 counts below 500/mm superscript 3, presence of anergy varied inversely with CD4 count. Anergy to both mumps and Candida was reported for approximately 80% of persons with CD4 counts <50/mm superscript 3.

In a multicenter National Institutes of Health (NIH) study of
pulmonary complications of acquired immunodeficiency syndrome
(AIDS),
1,240 patients infected with HIV are being followed (Markowitz N,
Henry Ford Hospital, personal communication). DTH responsiveness is
measured by mumps and Candida (trichophyton was removed from the
anergy panel because it elicited many fewer DTH responses than the
other two antigens). Results from this study showed a relation
between
anergy and CD4 counts, with increasing anergy at counts <400/mm superscript 3 and anergy among two-thirds of study subjects with counts <200/mm superscript 3. In general, DTH responsiveness was lower among intravenous drug users (IVDUs) than among patients in other HIV transmission categories. Candida and mumps antigens produced equivalent results and together elicited more responses than either antigen alone.

Several investigators have used the MULTITEST CMI(R) in studies
of
DTH responsiveness (3, Dassey D, Los Angeles County Health
Department,
personal communication). Based on varying criteria to define a
positive DTH response, anergy appears to be more common among HIV-
seropositive IVDUs than among HIV-seropositive persons who are in
other HIV transmission categories. Anergy is also more common among
persons infected with HIV who are asymptomatic than among
comparable
persons without HIV infection. Among the antigens included in this
test, Candida and tetanus toxoid produced the largest proportion of
positive DTH responses (generally defined as a reaction of greater
than or equal to 2 mm of induration).

There have been no comprehensive studies relating DTH respon-
siveness and biologic markers of HIV infection other than CD4
counts.
Although available information suggests that the CD4 count
correlates
highly with anergy, approximately 10% of asymptomatic persons with
early HIV infection and CD4 counts above 500/mm superscript 3 will
have no detectable DTH response to a panel of antigens, as will a
comparable percentage of apparently healthy persons without HIV
infection. Conversely, a small proportion of persons with
symptomatic,
advanced HIV disease and CD4 counts below 200/mm superscript 3 will
be
able to mount a DTH response.

STUDIES OF PPD TESTING IN HIV INFECTION

Studies conducted in various settings among persons with and
without HIV infection have suggested that HIV infection can depress
tuberculin reactions before signs and symptoms of HIV infection
develop.

In a study of HIV infection among postpartum women in Uganda,
27
(82%) of 33 HIV-seronegative women had reactions greater than or
equal
to 3 mm to Old Tuberculin (OT) as did 29 (48%) of 61
HIV-seropositive
women (4). The median reaction sizes for persons in the two groups
were 10.6 mm and 7.5 mm respectively (p

In an ongoing study of IVDUs in Baltimore, 31 (34%) of 90
seronegative persons were PPD positive (greater than or equal to 10
mm), compared with two (9%) of 22 seropositive persons (using
greater
than or equal to 5 mm to define a positive reaction) (p

Studies of tuberculosis disease associated with HIV infection
indicate that a substantial proportion of tuberculosis patients
will
have PPD anergy if their tuberculosis is concurrent with other HIV-
related opportunistic infections. In Florida, among patients who
were
reported to the tuberculosis and AIDS registers as having both
diseases, the probability of tuberculin anergy varied inversely
with
the interval between the diagnosis of tuberculosis and the
diagnosis
of AIDS decreased (7). In Los Angeles, 26 (55%) of 47 tuberculosis
patients who were HIV-seropositive had positive (greater than or
equal
to 5 mm) PPD responses; the mean CD4 count for the PPD-positive
patients was 220/mm superscript 3, compared with 66/mm superscript
3
for PPD-negative patients (Gutierrez G, Los Angeles County Health
Department, personal communication).

RECOMMENDATIONS FOR EVALUATION FOR ANERGY OF HIV-INFECTED PERSONS

Because of recent findings of apparent PPD anergy among
asymptomatic persons with HIV infection who have a high probability
of
tuberculous infection, persons with HIV infection should be
evaluated
for DTH anergy in conjunction with PPD testing. Emphasis for anergy
testing should be placed on persons who have an increased risk of
tuberculous infection (e,g,, IVDUs or those born in a country
endemic
for tuberculosis). Although HIV-infected persons who also have
evidence of immunosuppression (e,g., have had AIDS-defining
diagnoses
or total CD4 counts <500/mm superscript 3) have an increased probability of anergy, approximately 10% of asymptomatic persons with higher CD4 counts may also be anergic. Therefore, the degree of immunosuppression should not be a selective factor in considering a person for anergy testing. Anergy testing should also be considered for persons who are among risk groups for tuberculous and HIV co- infection but who refuse HIV testing.

Companion testing with two DTH skin-test antigens (i.e.,
Candida,
mumps, or tetanus toxoid), to which most healthy persons in the
population would be sensitized, is recommended. At present, mumps
antigen is the only product standardized for DTH to which most of
the
population would be expected to react. Although Candida antigen
also
performs satisfactorily, it is not yet licensed for DTH testing,
and
there may be lot-to-lot variation in potency and responsiveness.
Given
the apparently good performance of tetanus toxoid in DTH testing,
that
antigen may also be useful (a 5:1 dilution with phenol-buffered
diluent is commonly used). Because of the expectation that second
strength (250 TU), PPD tuberculin, would be less sensitive than the
other antigens in eliciting a DTH response, second strength PPD is
not
recommended for anergy evaluation; (nor is it recommended for
evalua-
tion for tuberculous infection). Although anergy testing with a
panel
of antigens administered by the multiple puncture method may give
useful results, it is costly and subject to the limitations
discussed
earlier,

Tests administered by the standard Mantoux method (0.1 ml) are
recommended to be given concurrently with a PPD tuberculin (5 TU)
skin
test. Rather than testing all HIV-seropositive individuals with an
anergy panel, anergy testing may be reserved for persons who are
found
to be tuberculin-negative. However, anergy testing at the time of
initial tuberculin testing is preferable, because of logistical
problems and nonadherence associated with repeat testing and
reading.
The skin test responses should be measured 48-72 hours after
administration. Any amount of induration to the DTH antigens is
considered evidence of DTH responsiveness; erythema alone is not
considered to be evidence of DTH responsiveness. Persons
unresponsive
to DTH (including PPD) are considered to be anergic.

ln general, persons with a positive DTH response to one or more
of
the DTH antigens but not to PPD tuberculin are not considered to be
infected with Mycobacterium tuberculosis. However, a negative PPD
reaction should never be used to exclude the diagnosis of active
tuberculosis, even among persons who react to other DTH antigens.
Reactions of greater than or equal to 5 mm to PPD are considered to
be
evidence of tuberculous infection, regardless of the reactions to
the
companion antigens.

The relation between CD4 count and prognosis for HIV-infection
has
been established. CD4 testing of all HIV-positive persons is
recomm-
ended for determining the degree of HIV immunosuppression and for
deciding about the need for other treatment measures (e.g.,
zidovudine, Pneumocystis carinii pneumonia {PCP} prophylaxis).
However, CD4 testing is not a substitute for anergy testing. At
present, other surrogate markers of HIV infection (e.g., serum
neopterin, beta-2-microglobulin, p24 antigen) are not helpful in
this
regard.

MANAGEMENT OF ANERGIC, HIV-INFECTED PERSONS

CDC and the American Thoracic Society recommend that tuberculin
reactions greater than or equal to 5 mm be considered positive for
persons who are HIV-seropositive (regardless of Bacillus of
Calmette
and Guerin {BCG} vaccination status) and that such persons be
considered for isoniazid prophylaxis (1). On the basis of data
cited
earlier, persons infected with HIV who have negative tuberculin
skin-
test reactions (i.e., <5 mm) and anergy as defined earlier may also need to be considered for isoniazid preventive therapy based on an individual clinical and epidemiologic assessment of the likelihood of infection with M. tuberculosis.

Preventive therapy should be considered for anergic persons who
are known contacts of infectious tuberculosis patients and for
those
from groups in which the prevalence of tuberculous infection is
greater than or equal to 10%. This recommendation is based on
suggested marked benefit from isoniazid preventive therapy among
IVDUs
who are HIV-infected and who have negative tuberculin skin test
reactions (8). Presumably, those IVDUs who are also anergic would
achieve an even greater benefit from preventive therapy.

In the United States, groups at increased risk of tuberculosis
include IVDUs, prisoners, homeless persons, migrant laborers, and
persons born in countries in Asia, Africa, and Latin America with
high
rates of tuberculosis (9). Infection rates among these groups are
generally greater than or equal to 10%. All such persons should be
carefully evaluated for active tuberculosis (with a chest
radiograph
and clinical assessment) before beginning preventive therapy.

Anergic persons who are at increased risk for tuberculosis but
elect not to take isoniazid preventive therapy should be carefully
educated about the signs and symptoms of tuberculosis in HIV
infection. They should be instructed to promptly seek medical
assessment should any of these signs or symptoms develop.

RESEARCH PRIORITIES

Further studies to define the relation between anergy and co-
infection with HIV and M. tuberculosis are needed. Studies that
will
more accurately define the risk of tuberculosis among persons
infected
with HIV who are anergic are especially important. Studies are also
needed to determine the usefulness of repeating anergy tests (e.g.,
2-
step testing as is suggested for certain persons being PPD tested).
For these studies, only a single lot of any DTH antigen preparation
should be used, and the investigator should be aware that changes
in
lots or manufacturer may result in antigens of markedly different
potencies. This may result in misinterpretation of cellular hyper-
sensitivity status if a patient is being monitored periodically
with
such antigens, or may introduce bias when comparing groups of
patients
tested with different lots or products from different
manufacturers.
Finally there are needs for accurate surrogate tests for anergy and
more sensitive tests to determine the presence of tuberculous
infection among anergic persons.

References

CDC. Tuberculosis and human immunodeficiency virus infection:
recommendations of the Advisory Committee for the Elimination
of
Tuberculosis (ACET). MMWR 1989;38:236-8,243-50.

All persons with HIV infection should receive a PPD-tuberculin
skin test (5TU, PPD by Mantoux method).

Because of the occurrence of anergy to PPD among persons with
HIV
infection at risk of tuberculosis, persons with HIV infection
should also be evaluated for DTH anergy at the time of PPD
testing.

Companion testing with two DTH antigens (Candida, mumps, or
tetanus toxoid) administered by the Mantoux method is
recommended.
However, a multipuncture device which administers a battery of
DTH
antigens may be used.

Any induration to a DTH antigen measured at 48 hours to 72
hours
is considered evidence of DTH responsiveness; failure to elicit
a
response is considered evidence of anergy.

Those persons with a positive (greater than or equal to 5mm
induration) PPD reaction are considered to be infected with M.
tuberculosis and should be evaluated for isoniazid preventive
therapy after active tuberculosis has been excluded.

Persons who manifest a DTH response but have a negative PPD
reaction are, in general, considered not to be infected with M.
tuberculosis.

Anergic, tuberculin-negative persons whose risk of tuberculous
infection is estimated to be greater than or equal to 10%
should
also be considered for isoniazid preventive therapy after
active
tuberculosis is excluded.

Although CD4 counts should be performed as a part of the evalu-
ation and management of persons with HIV infection, this
measurement is not a substitute for anergy evaluation.

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